US10118937B1 - Process for preparing ixazomib citrate and intermediates therefor - Google Patents
Process for preparing ixazomib citrate and intermediates therefor Download PDFInfo
- Publication number
- US10118937B1 US10118937B1 US15/860,949 US201815860949A US10118937B1 US 10118937 B1 US10118937 B1 US 10118937B1 US 201815860949 A US201815860949 A US 201815860949A US 10118937 B1 US10118937 B1 US 10118937B1
- Authority
- US
- United States
- Prior art keywords
- formula
- compound
- protecting group
- tert
- ixazomib citrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- MBOMYENWWXQSNW-AWEZNQCLSA-N ixazomib citrate Chemical compound N([C@@H](CC(C)C)B1OC(CC(O)=O)(CC(O)=O)C(=O)O1)C(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MBOMYENWWXQSNW-AWEZNQCLSA-N 0.000 title claims abstract description 27
- 229960002951 ixazomib citrate Drugs 0.000 title claims abstract description 24
- 239000000543 intermediate Substances 0.000 title description 12
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000008569 process Effects 0.000 claims abstract description 21
- 150000001408 amides Chemical group 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- -1 triethylsilyl Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- MLOOZVZNJWMEEW-UHFFFAOYSA-N OBO.OC(=O)C(F)(F)F Chemical compound OBO.OC(=O)C(F)(F)F MLOOZVZNJWMEEW-UHFFFAOYSA-N 0.000 claims description 5
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 0 *N(CC(=O)C[C@@H](CC(C)C)B(F)(F)F)C(=O)C1=CC(Cl)=CC=C1Cl.*N(CC(=O)C[C@@H](CC(C)C)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1)C(=O)C1=C(Cl)C=CC(Cl)=C1.[KH].[V].[V]I Chemical compound *N(CC(=O)C[C@@H](CC(C)C)B(F)(F)F)C(=O)C1=CC(Cl)=CC=C1Cl.*N(CC(=O)C[C@@H](CC(C)C)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1)C(=O)C1=C(Cl)C=CC(Cl)=C1.[KH].[V].[V]I 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- LEKWSVFJAJFROX-UHFFFAOYSA-N 2-[(2,5-dichlorobenzoyl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound CC(C)(C)OC(=O)N(CC(O)=O)C(=O)c1cc(Cl)ccc1Cl LEKWSVFJAJFROX-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000004809 Teflon Substances 0.000 description 5
- 229920006362 Teflon® Polymers 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 5
- 229960004106 citric acid Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229960003648 ixazomib Drugs 0.000 description 5
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- KHJXBZKWWGWNCB-UHFFFAOYSA-N benzyl 2-[(2,5-dichlorobenzoyl)amino]acetate Chemical compound ClC1=CC=C(Cl)C(C(=O)NCC(=O)OCC=2C=CC=CC=2)=C1 KHJXBZKWWGWNCB-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 108010016626 Dipeptides Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- ZRPVCMVFSGTTLH-UHFFFAOYSA-N benzyl 2-[(2,5-dichlorobenzoyl)-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetate Chemical compound CC(C)(C)OC(=O)N(CC(=O)OCc1ccccc1)C(=O)c1cc(Cl)ccc1Cl ZRPVCMVFSGTTLH-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HKUAUZSWGMQPOK-UHFFFAOYSA-N 2-[(2,5-dichlorobenzoyl)amino]acetic acid Chemical compound OC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl HKUAUZSWGMQPOK-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- KCSXSJLLFFWXCJ-UHFFFAOYSA-N C.CC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl.I.O=C(O)CNC(=O)C1=CC(Cl)=CC=C1Cl Chemical compound C.CC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl.I.O=C(O)CNC(=O)C1=CC(Cl)=CC=C1Cl KCSXSJLLFFWXCJ-UHFFFAOYSA-N 0.000 description 2
- PGKMQCKBYDFIPY-UHFFFAOYSA-N CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl.CN(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.II.I[IH]I Chemical compound CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl.CN(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.II.I[IH]I PGKMQCKBYDFIPY-UHFFFAOYSA-N 0.000 description 2
- FCTZEVWVLMHZAS-LTKBAGSJSA-K CC(C)C[C@H](C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CN(CC(=O)O)C(=O)C1=CC(Cl)=CC=C1Cl.I[IH]I.I[V]I.[V]I Chemical compound CC(C)C[C@H](C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CN(CC(=O)O)C(=O)C1=CC(Cl)=CC=C1Cl.I[IH]I.I[V]I.[V]I FCTZEVWVLMHZAS-LTKBAGSJSA-K 0.000 description 2
- MDIWPWAJYCNXCY-UHXHHCAISA-M CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B(F)(F)F.CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.[KH].[V].[V]I Chemical compound CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B(F)(F)F.CC(C)C[C@H](CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.[KH].[V].[V]I MDIWPWAJYCNXCY-UHXHHCAISA-M 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 101710094502 Proteasome subunit beta type-5 Proteins 0.000 description 2
- 102100036127 Proteasome subunit beta type-5 Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- COERJHDMQUPDCV-UHFFFAOYSA-N [K].FB(F)F Chemical class [K].FB(F)F COERJHDMQUPDCV-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229940030115 ninlaro Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RSINFFVFOTUDEC-UHFFFAOYSA-N 2,5-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC=C1Cl RSINFFVFOTUDEC-UHFFFAOYSA-N 0.000 description 1
- ASZZHBXPMOVHCU-UHFFFAOYSA-N 3,9-diazaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)NC(=O)CC11CCNCC1 ASZZHBXPMOVHCU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- HSKFKISAQXHLLZ-NHLLJQSTSA-L C.C.C.C.C.CC(C)(C)OC(=O)N(CC(=O)O)C(=O)C1=CC(Cl)=CC=C1Cl.CC(C)(C)OC(=O)N(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.CC(C)C[C@H](CC(=O)CN(C(=O)OC(C)(C)C)C(=O)C1=CC(Cl)=CC=C1Cl)B(F)(F)F.CC(C)C[C@H](CC(=O)CN(C(=O)OC(C)(C)C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.I.I[V]I.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1.O=C(O)CNC(=O)C1=CC(Cl)=CC=C1Cl.[KH] Chemical compound C.C.C.C.C.CC(C)(C)OC(=O)N(CC(=O)O)C(=O)C1=CC(Cl)=CC=C1Cl.CC(C)(C)OC(=O)N(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.CC(C)C[C@H](CC(=O)CN(C(=O)OC(C)(C)C)C(=O)C1=CC(Cl)=CC=C1Cl)B(F)(F)F.CC(C)C[C@H](CC(=O)CN(C(=O)OC(C)(C)C)C(=O)C1=CC(Cl)=CC=C1Cl)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.I.I[V]I.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1.O=C(O)CNC(=O)C1=CC(Cl)=CC=C1Cl.[KH] HSKFKISAQXHLLZ-NHLLJQSTSA-L 0.000 description 1
- WMZNEZOJDHWTBT-UTONKHPSSA-N C.[H]N(CC(=O)C[C@@H](CC(C)C)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1)C(=O)C1=C(Cl)C=CC(Cl)=C1 Chemical compound C.[H]N(CC(=O)C[C@@H](CC(C)C)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1)C(=O)C1=C(Cl)C=CC(Cl)=C1 WMZNEZOJDHWTBT-UTONKHPSSA-N 0.000 description 1
- MTYUWTCKBXOJQH-UHFFFAOYSA-N CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl.I.II.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1 Chemical compound CC(=O)CN(C)C(=O)C1=CC(Cl)=CC=C1Cl.I.II.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1 MTYUWTCKBXOJQH-UHFFFAOYSA-N 0.000 description 1
- CDNKLNIOIDYIAH-GXNLIMDKSA-N CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B(O)O.CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1.CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.COB(C)[C@@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)CC(C)C.Cl.NCC(=O)O.O=C(Cl)C1=C(Cl)C=CC(Cl)=C1.O=C(O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1 Chemical compound CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B(O)O.CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B1OC(=O)C(CC(=O)O)(CC(=O)O)O1.CC(C)C[C@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1.COB(C)[C@@H](CC(=O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1)CC(C)C.Cl.NCC(=O)O.O=C(Cl)C1=C(Cl)C=CC(Cl)=C1.O=C(O)CNC(=O)C1=C(Cl)C=CC(Cl)=C1 CDNKLNIOIDYIAH-GXNLIMDKSA-N 0.000 description 1
- ITKYCSWRJQCAOS-ILRUXTBWSA-N CCC1(CC(=O)O)OB([C@@H](CC(=O)CNC(=O)C2=C(Cl)C=CC(Cl)=C2)CC(C)C)OC1=O Chemical compound CCC1(CC(=O)O)OB([C@@H](CC(=O)CNC(=O)C2=C(Cl)C=CC(Cl)=C2)CC(C)C)OC1=O ITKYCSWRJQCAOS-ILRUXTBWSA-N 0.000 description 1
- RMUZUSIHOTXXBD-UHFFFAOYSA-N CN(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.I.II.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1 Chemical compound CN(CC(=O)OCC1=CC=CC=C1)C(=O)C1=CC(Cl)=CC=C1Cl.I.II.O=C(CNC(=O)C1=CC(Cl)=CC=C1Cl)OCC1=CC=CC=C1 RMUZUSIHOTXXBD-UHFFFAOYSA-N 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- NJNMTSPYZYHSHZ-UHFFFAOYSA-N O1BOC(C1)(CC(=O)O)CC(=O)O Chemical group O1BOC(C1)(CC(=O)O)CC(=O)O NJNMTSPYZYHSHZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- BRTALTYTFFNPAC-UHFFFAOYSA-N boroxin Chemical compound B1OBOBO1 BRTALTYTFFNPAC-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the present application relates to a process for preparation of ixazomib citrate and intermediates therefor.
- NINLARO is an antineoplastic agent.
- Ixazomib citrate a prodrug, rapidly hydrolyzes under physiological conditions to its biologically active form, ixazomib.
- the chemical name of ixazomib citrate is 1,3,2-dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-, and the structural formula is:
- the molecular formula for ixazomib citrate is C 20 H 23 BC 12 N 2 O 9 , and its molecular weight is 517.12.
- NINLARO ixazomib
- ixazomib is a proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
- ixazomib citrate is the first oral PI approved by US Food and Drug Administration.
- ixazomib citrate is a peptide analogue that reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5), which is part of the 20S proteasome complex.
- PSMB5 protein proteasome subunit beta type-5
- ixazomib citrate has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in controlling the myeloma growth and preventing the bone loss.
- U.S. Pat. No. 9,175,018 discloses that the synthesis of ixazomib citrate commences from commercially available 2,5-dichlorobenzoyl chloride i, which is reacted with glycine under basic condition to afford the corresponding dipeptide ii. Subsequent coupling the dipeptide ii with boronate trifluoroacetate salt provides the protected boronate iii. Deprotection of iii under acidic condition gives the intermediate iv or v. In the last step, the intermediate iv or v is subjected to esterification with citric acid at a temperature of 60° C. Upon cooling to ambient temperature, the final ixazomib citrate product is isolated as a white solid.
- the present invention relates to a method for preparing Ixazomib citrate and intermediates therefor.
- the first aspect of the present invention is a process for making ixazomib citrate of formula VI comprising reacting a compound of formula V with citric acid to form ixazomib citrate of formula VI:
- R is hydrogen or an amide protecting group.
- the reacting step may be conducted under any appropriate conditions, for example, at a temperate from 0 to 80° C., preferably 50 to 70° C. for 1 to 30 hours, preferably 12 to 20 hours.
- the process further comprises a step of fluorinating a compound of formula IV to provide the compound of formula V:
- the fluorinating step may be conducted may be conducted under any appropriate conditions, for example, at a temperate from 10 to 50° C., preferably 20 to 30° C. for 10 to 30 hours, preferably 15 to 20 hours.
- the amide protecting group in accordance with the present invention is preferably selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butoxycarbonyl (Boc), and 9-Fluorenylmethoxycarbonyl (Fmoc) groups.
- the second aspect of the present invention is an organotrifluoroborate salt of formula V,
- R is hydrogen or an amide protecting group
- the third aspect of the present invention is a process for making a compound of formula V comprising:
- R′ is hydrogen or an amide protecting group.
- the fluorinating step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 50° C., preferably 20 to 30° C. for 10 to 30 hours, preferably 15 to 20 hours.
- the process further comprises coupling a compound of formula III with a boronate trifluoroacetate salt of formula VII to provide the compound of formula IV:
- This coupling step may be conducted under any appropriate conditions, for example, at a temperate from ⁇ 20 to 20° C., preferably 0 to 5° C. for 1 to 10 hours, preferably 2 to 5 hours.
- the process may further comprise reducing a compound of formula II to provide the compound of formula III:
- This reducing step may be conducted under any appropriate conditions, for example, at a temperate from 0 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
- the process may further comprise protecting a compound of formula I to provide the compound of formula II:
- R′ is the amide protecting group.
- This protecting step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
- the process may also further comprise a step of benzylating a compound of formula ii to provide the compound of formula I
- This benzylating step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
- protecting group refers to a moiety that is formed to render a functional moiety unreactive.
- the protecting group can be removed so as to restore the functional moiety to its original state.
- Various protecting groups and protecting reagents, including amide protecting groups are well known to one of ordinary skill in the art and include compounds that are disclosed in Protective Groups in Organic Synthesis, 4th edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.
- a route via intermediate V as shown in Scheme 2 below is used for the preparation of ixazomib citrate.
- the intermediate V an organotrifluoroborate salt, has the following advantages in synthetic chemistry: i) it can be easily prepared and easily purified by recrystallization; ii) it is generally air and moisture stable at ambient temperature; iii) it has defined stoichiometric of reagents for next transformation step; and iv) it is tolerant of a broad range of functional groups and leads to non-toxic by-products.
- the synthesis of ixazomib citrate in accordance with an embodiment of the present invention commences from commercially available dipeptide I, which is transformed to the acid III through the protection of I followed by reduction of the resulted benzyl ester II to the acid of III. Subsequent coupling the acid III with boronate trifluoroacetate salt provides the protected boronate IV, wherein R is an amide protecting group. Deprotection of IV via fluorinating condition provides the intermediate V which is subjected to esterification with citric acid to form the citrate VI. Deprotection of citrate VI provides ixazomib citrate isolated as a white solid.
- the borontrifluoride intermediate, organotrifluoroborate salt shows exceptional stabilities toward nucleophilic compounds as well as air and moisture, which offer a stable alternative to commonly used organoboron compounds.
- the organotrifluoroborate salt can be stored under normal atmospheric conditions for extended periods without noticeable degradation or decomposition as compared to some of their boronic acid, boronate ester, and haloborane counterparts. 2.
- Generally common borontrifluorides have the limitation of being insoluble in organic media, and require polar solvents like MeCN and H 2 O at elevated temperatures for dissolution.
- protecting group R is used in intermediate of formula V for the added advantage of being readily soluble in organic media, which made the subsequent citrate formation easier and faster.
- the obtained wet cake was added n-heptane (10 mL), strongly stirred for 10 minutes and the resulted slurry was filtered.
- the obtained wet cake was added n-heptane (10 mL), strongly stirred for 10 minutes and the resulted slurry was filtered.
- the cake was washed by n-heptane (10 mL) and dried under vacuum to give the desired potassium borontrifluoride salts (vi) (376.2 mg) in 97% yield.
- the resulted white slurry mixture was added the solution of citric acid monohydrate (52.3 mg, 0.25 mmol, 1.00 equiv.) in ethyl acetate (3 mL) at 20 to 30° C. The slurry was then heated at 65° C. After stirring for 2 hrs, the reaction mixture was slowly cooled to 20 to 30° C. and stirred for 16 hrs. The resulting mixture was filtered under N 2 and the filtrate was concentrated to give yellow oil which was directly used for the next step without purification.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Abstract
Description
The fluorinating step may be conducted may be conducted under any appropriate conditions, for example, at a temperate from 10 to 50° C., preferably 20 to 30° C. for 10 to 30 hours, preferably 15 to 20 hours.
-
- fluorinating a compound of formula IV to form the compound of formula V;
wherein R′ is hydrogen or an amide protecting group. The fluorinating step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 50° C., preferably 20 to 30° C. for 10 to 30 hours, preferably 15 to 20 hours.
This coupling step may be conducted under any appropriate conditions, for example, at a temperate from −20 to 20° C., preferably 0 to 5° C. for 1 to 10 hours, preferably 2 to 5 hours.
This reducing step may be conducted under any appropriate conditions, for example, at a temperate from 0 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
wherein R′ is the amide protecting group. This protecting step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
This benzylating step may be conducted under any appropriate conditions, for example, at a temperate from 10 to 40° C., preferably 20 to 30° C. for 10 to 40 hours, preferably 10 to 20 hours.
Relevant | Advantage of the | |||
information to | Embodiments of | embodiments of this | ||
Reference | this invention | this Invention | Differences | invention |
U.S. | Formation of | Formation of | 1. Different | 1. Organoboranes |
Pat. No. | ixazomib | ixazomib citrate is | intermediates | shown in e.g., U.S. |
9,175,018 | citrate is | achieved through | are employed. | Pat. No. 9,175,018 B2 are |
achieved | the reaction | 2. Novel | generally not stable | |
through the | between a | transformation | under atmospheric | |
condensation | potassium | is applied. | conditions, particularly | |
reaction | borontrifluoride | alkyl- and | ||
between a | and citric acid | alkynylboranes. The | ||
boronic acid | followed by a | lack of stability of | ||
(e.g., | deprotection | organoboranes is due | ||
ixazomib) and | reaction. | to the vacant orbital on | ||
citric acid. | boron, which can be | |||
attacked by oxygen or | ||||
water, resulting in | ||||
decomposition of the | ||||
reagent. Based on the | ||||
embodiments of the | ||||
present invention, the | ||||
borontrifluoride | ||||
intermediate, | ||||
organotrifluoroborate | ||||
salt shows exceptional | ||||
stabilities toward | ||||
nucleophilic compounds | ||||
as well as air and | ||||
moisture, which offer a | ||||
stable alternative to | ||||
commonly used | ||||
organoboron | ||||
compounds. The | ||||
organotrifluoroborate | ||||
salt can be stored under | ||||
normal atmospheric | ||||
conditions for extended | ||||
periods without | ||||
noticeable degradation | ||||
or decomposition as | ||||
compared to some of | ||||
their boronic acid, | ||||
boronate ester, and | ||||
haloborane counterparts. | ||||
2. Generally common | ||||
borontrifluorides have | ||||
the limitation of being | ||||
insoluble in organic | ||||
media, and require | ||||
polar solvents like | ||||
MeCN and H2O at | ||||
elevated temperatures | ||||
for dissolution. Based | ||||
on the embodiments of | ||||
this invention, | ||||
protecting group R is | ||||
used in intermediate of | ||||
formula V for the added | ||||
advantage of being | ||||
readily soluble in | ||||
organic media, which | ||||
made the subsequent | ||||
citrate formation easier | ||||
and faster. | ||||
Claims (11)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/860,949 US10118937B1 (en) | 2018-01-03 | 2018-01-03 | Process for preparing ixazomib citrate and intermediates therefor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/860,949 US10118937B1 (en) | 2018-01-03 | 2018-01-03 | Process for preparing ixazomib citrate and intermediates therefor |
Publications (1)
Publication Number | Publication Date |
---|---|
US10118937B1 true US10118937B1 (en) | 2018-11-06 |
Family
ID=63964529
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/860,949 Expired - Fee Related US10118937B1 (en) | 2018-01-03 | 2018-01-03 | Process for preparing ixazomib citrate and intermediates therefor |
Country Status (1)
Country | Link |
---|---|
US (1) | US10118937B1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140343314A1 (en) | 2008-06-17 | 2014-11-20 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
-
2018
- 2018-01-03 US US15/860,949 patent/US10118937B1/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140343314A1 (en) | 2008-06-17 | 2014-11-20 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
US9175018B2 (en) | 2008-06-17 | 2015-11-03 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10899745B2 (en) | Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide | |
US9162974B2 (en) | Process for the preparation of vorinostat | |
AU2200199A (en) | Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors | |
ES2901701T3 (en) | Method for preparing 4-methoxypyrrole derivative intermediate | |
US8884009B2 (en) | Process for making bortezomib and intermediates for the process | |
US4426391A (en) | [(Alkoxycarbonyl)oxy]alkyl esters of methyldopa | |
US20080076923A1 (en) | Process for the preparation and purification of valgancyclovir | |
US8134026B2 (en) | Process for the preparation of Cilastatin and sodium salt | |
JPH0853452A (en) | Achiral amino acid acyl ester of gancyclobyl and its derivative | |
US9505787B2 (en) | Process for preparing of bortezomib | |
US20110124899A1 (en) | Method for preparing combretastatin | |
US20220324799A1 (en) | Compositions of trofinetide | |
JP4158192B2 (en) | Method for producing acylphenylalanine | |
US10118937B1 (en) | Process for preparing ixazomib citrate and intermediates therefor | |
IE850518L (en) | Guanidine derivatives. | |
US20110039937A1 (en) | Novel process for the preparation of vorinostat | |
US20230128167A1 (en) | Oligopeptide linker intermediate and preparation method thereof | |
JP3891503B2 (en) | Improved tolerance of pharmaceutically active β-amino acids | |
CA2453245A1 (en) | Fluoro linkers and their use as linkers for enzyme-activated drug conjugates | |
US8853453B2 (en) | Processes for reducing impurities in lacosamide | |
KR101772898B1 (en) | Improved method of sitagliptin | |
EP0973726B1 (en) | Method for synthesis of rhizoferrin | |
US20190309017A1 (en) | Glutaminase inhibitors | |
US8664443B2 (en) | Process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile | |
US20140296520A1 (en) | Process for the preparation of valacyclovir hydrochloride |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20221106 |